Nowadays, the number of dialysis patients are increasing, and it is presumed that the number of such patients will be enormous when taking into account the number of diabetic patients who will be in need of dialysis in the future, and the medical expenses for dialysis is estimated to be well over 1 trillion yen. Considering these situations, preventive medicine that prevents the onset of renal diseases and conservative treatments that prevent the progress of renal failure into dialysis are regarded important. Effective treatments of renal disorders in patients of chronic renal failure have not been established yet, treatments including low protein diet therapy and the administration of antihypertensive drugs such as an ACE inhibitor have been conducted so far (Am. J. Cardiol. 59, 66A-71A, 1987; Am. J. Kidney. 20, 443-57, 1992; BMJ 304, 216-20, 1992; Ann. Intern. Med. 124, 627-32, 1996). The above-mentioned low protein diet therapy is thought to be effective means to suppress the progress of chronic renal failure and is widely conducted currently. However, since dietary restriction contains problems of quality of life (QOL) and compliance of patients, a new therapeutic strategy, for example, suppression of oral protein absorption, is needed. Recently, as a new strategy for the treatment of hyperlipemia, it is reported that biosynthesis of cholesterol is suppressed by inhibiting a bile acid transporter present in the small intestine, and this report draws attention (J. Pharmacol. Exp. Ther. 293, 315-20 2000). Likewise, it is expected that the absorption of proteins through the digestive tract can be suppressed by a specific inhibitor.
The present inventors have reported that proteins taken are digested in the digestive tract to amino acids and oligopeptides and absorbed through the small intestine, and that the absorption is conducted by a specific transporter present in the brush border membrane of a small intestine epithelial cell (Pharm. Res. 13, 963-77, 1996). The digested amino acids mentioned above are transported by multiple transporters, however, the oligopeptides are transported by an oligopeptide transporter such as PEPT 1, and absorbed dipeptide- or tripeptide-specifically (J. Biol. Chem. 270, 6456-63, 1995). As to the absorption of digestive products of proteins in the small intestine, it is known that more peptides are absorbed than amino acids (Gastroenterology 113, 332-40, 1997). Taken together, it is considered that a PEPT 1 inhibitor is capable of suppressing the absorption of proteins in the diet, and is useful for the patients whose QOL is deteriorated due to diet therapy.
Since 1994, PEPT 1 genes have been cloned from small intestines of rabbit, human and rat (J. Biol. Chem. 270, 6456-63, 1995; Nature 368, 563-6, 1994; J. Pharma. Exp. Ther. 275, 1631-7, 1995; Biochim. Biophys. Acta, 1305, 34-8, 1996), and studies for transportation via PEPT 1 have been rapidly developed. The above-mentioned PEPT 1 gene derived from rat small intestine has been cloned for the first time by the present inventors (Biochim. Biophys. Acta, 1305, 34-8, 1996), and revealed to locate in the brush border membrane side of the small intestine epithelial cell by immunohistochemical technique (FEBS Lett. 392, 25-9, 1996). In addition, it is reported that PEPT 1 recognizes and transports compounds such as valacyclovir, an antiviral drug, that does not have a peptide bond in its molecules, as well as compounds having peptide-like structures, for example, β-lactam antibiotics (Pharm. Res. 13, 963-77, 1996; Biochem. Biophys. Res. Commun. 250, 246-51, 1998; J. Clin. Invest. 101, 2761-7, 1998; J. Biol. Chem. 273, 20-2, 1998). As mentioned above, PEPT 1 shows wide range of substrate recognition property, however, its molecular recognition property remains unknown and it is thought that the substrate recognition of PEPT 1 involves not only the recognition of partial structure but also whole molecule. Meanwhile, PEPT 2, which is cloned from the kidney (Biochim. Biophys. Acta, 1235, 461-6, 1995; Biochim. Biophys. Acta, 1280, 173-7, 1996; Proc. Natl. Acad. Sci. USA 93, 284-9, 1996), locates in the brush border membrane side of the epithelial cell in the proximal convoluted tubule of the kidney, and has a substrate recognition property similar to that of PEPT 1, and serves to reabsorbing oligopeptides and peptide-like compounds. The above-mentioned PEPT 1 is known to express in the kidney though it does not contribute very much (Am. J. Physiol. 276, F658-65, 1999). However, PEPT 2 has never been observed to express in the small intestine.
In human, it is reported that bioavailability (BA) of cefadroxil (CDX), a β-lactam antibiotic and a substrate of PEPT 1, is decreased by co administration of cephalexin (CEX), a β-lactam antibiotic similarly recognized by PEPT 1 (Eur. J. Clin. Pharmacol. 41, 179-83, 1991). A mechanism in which AUC (Area Under the plasma concentration Curve) as an index of bioavailability is decreased by CEX includes both the absorption of CDX in the small intestine and the inhibition of reabsorption of CDX in the kidney. The reabsorption through the kidney is conducted mainly via an oligopeptide transporter (PEPT 2), and both compounds are known to be substrates for PEPT 2 (Biochim. Biophys. Acta, 1235, 461-6, 1995). Therefore, it is explicable that the decrease of BA of CDX caused by CEX means that CDX transportation via PEPT 1 and PEPT 2 is inhibited by CEX. Though the effect of the inhibition of PEPT 2 present in the kidney on a living organism is unknown, it seems preferable to limit to a direct inhibition of absorption via PEPT 1 from the viewpoint of diet therapy for chronic renal failure. However, since PEPT 1 and PEPT 2 show very similar substrate recognition properties, it has been presumed to be difficult to develop an inhibitor which specifically recognizes PEPT 1.
The number of dialysis patients due to renal failure are increasing, and it is presumed that the number of such patients will be enormous when taking into account the number of diabetic patients who will be in need of dialysis, and the medical expenses for dialysis is estimated to be well over 1 trillion yen in the future. Under these circumstances, preventive medicine that prevents the onset of renal diseases and conservative treatments that prevent the progress of renal failure into dialysis are important. The object of the present invention is to provide a tissue-specific transporter inhibitor which is not absorbed through the digestive tract and can prevent deterioration in the QOL of patients caused by diet therapy, and a therapeutic drug for tissue dysfunction diseases and a therapeutic drug for suppressing the progress of chronic renal failure containing the inhibitor as an active ingredient.
The present inventors have considered that it is effective to use a PEPT 1 inhibitor which is not absorbed through the digestive tract and is able to avoid recognizing PEPT 2 in order to attain the above-mentioned object, and that PEPT 1 can be selectively inhibited by designing a polymer compound having PEPT 1 recognition property because polymer compounds are not absorbed through the digestive tract in general. Therefore, the present inventors have focused on a supramolecular structure polyrotaxane (PRX) wherein its structurally modified active residue is expected to be excellent in the interaction with a transmembrane transporter, and constructed a compound wherein a dipeptide (Val-Lys) which is a ligand of the PEPT 1 mentioned above is introduced into a supramolecular structure PRX. As a result of intensive study, it has been found that the above-mentioned compound can suppress the absorption of proteins and the progress of chronic renal failure which needs limitation of protein uptake, and thus the present invention has been completed.